title: Human cytomegalovirus tegument protein pp150 acts as a cyclin A2-CDK-dependent sensor of the host cell cycle and differentiation state.
abstract: Upon cell entry, herpesviruses deliver a multitude of premade virion proteins to their hosts. The interplay between these incoming proteins and cell-specific regulatory factors dictates the outcome of infections at the cellular level. Here, we report a unique type of virion-host cell interaction that is essential for the cell cycle and differentiation state-dependent onset of human cytomegalovirus (HCMV) lytic gene expression. The major tegument 150-kDa phosphoprotein (pp150) of HCMV binds to cyclin A2 via a functional RXL/Cy motif resulting in its cyclin A2-dependent phosphorylation. Alanine substitution of the RXL/Cy motif prevents this interaction and allows the virus to fully escape the cyclin-dependent kinase (CDK)-mediated block of immediate early (IE) gene expression in S/G2 phase that normally restricts the onset of the HCMV replication cycle to G0/G1. Furthermore, the cyclin A2-CDK-pp150 axis is also involved in the establishment of HCMV quiescence in NTera2 cells, showing the importance of this molecular switch for differentiation state-dependent regulation of IE gene expression. Consistent with the known nucleocapsid-binding function of pp150, its RXL/Cy-dependent phosphorylation affects gene expression of the parental virion only, suggesting a cis-acting, virus particle-associated mechanism of control. The pp150 homologs of other primate and mammalian CMVs lack an RXL/Cy motif and accordingly even the nearest relative of HCMV, chimpanzee CMV, starts its lytic cycle in a cell cycle-independent manner. Thus, HCMV has evolved a molecular sensor for cyclin A2-CDK activity to restrict its IE gene expression program as a unique level of self-limitation and adaptation to its human host.
authors.affiliation: Labor für Pädiatrische Molekularbiologie, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Bogdanow
authors.forename: Henry
authors.initials: H
authors.lastname: Weisbach
authors.forename: Jens
authors.initials: J
authors.lastname: von Einem
authors.forename: Sarah
authors.initials: S
authors.lastname: Straschewski
authors.forename: Sebastian
authors.initials: S
authors.lastname: Voigt
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.forename: Christian
authors.initials: C
authors.lastname: Hagemeier
authors.forename: Lüder
authors.initials: L
authors.lastname: Wiebusch
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early / Q000235:genetics; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056751:Cyclin A2; D008164:Luminescent Proteins; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C056367:pp150 protein, Cytomegalovirus; D018844:Cyclin-Dependent Kinases